This invention relates to methods of treating cyclooxygenase mediated diseases and certain pharmaceutical compositions therefor.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme, as originally identified in bovine seminal vesicles. More recently the gene for a second inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, COX-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, COX-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of COX-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
Furthermore, such a compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labour, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, for decreasing bone loss particularly in postmenopausal women (i.e. treatment of osteoporosis) and for the treatment of glaucoma.
The potential utilities of selective cyclooxygenase-2 inhibitors are discussed in the following articles:
1. John Vane, "Towards a better aspirin" in Nature, Vol. 367, pp. 215-216, 1994 PA1 2. Bruno Battistini, Regina Botting and Y. S. Bakhle, "COX-1 and COX-2: Toward the Development of More Selective NSAIDs" in Drug News and Perspectives, Vol. 7, pp. 501-512, 1994. PA1 3. David B. Reitz and Karen Seibert, "Selective Cyclooxygenase Inhibitors" in Annual Reports in Medicinal Chemistry. James A. Bristol, Editor, Vol. 30, pp. 179-188, 1995. PA1 R.sup.2 is a mono-, di-, or tri-substituted pyridinyl, wherein the substituents are chosen from the group consisting of PA1 R.sup.3 and R.sup.4 are independently chosen from the group consisting of PA1 or R.sup.3 and R.sup.4 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms. PA1 (a) hydrogen, PA1 (b) halo, PA1 (c) C.sub.1-6 alkoxy, PA1 (d) C.sub.1-6 alkylthio, PA1 (e) C.sub.1-6 alkyl, PA1 (f) CF.sub.3, PA1 (g) CN. PA1 AA=arachidonic acid PA1 Ac=acetyl PA1 AIBN=2.2--azobisisobutyronitrile PA1 BHT=butylated hydroxytoluene PA1 Bn=benzyl PA1 dba=dibenzylideneacetone PA1 DMAP=4-(dimethylamino)pyridine PA1 DMF=N,N-dimethylformamide PA1 DMSO=dimethyl sulfoxide PA1 EDTA=ethylenediaminetetraacetic acid PA1 Et.sub.3 N=triethylamine PA1 HBSS=Hanks balanced salt solution PA1 HEPES=N-2-Hydroxyethyl!piperazine-N.sup.1 -2-ethanesulfonic acid! PA1 HWB=human whole blood PA1 KHMDS=potassium hexamethyldisilazane PA1 LDA=lithium diisopropylamide PA1 LPS =lipopolysaccharide PA1 MMPP=magnesium monoperoxyphthalate PA1 Ms=methanesulfonyl=mesyl PA1 Ms0=methanesulfonate=mesylate PA1 NBS=N-bromosuccinimide PA1 NCS=N-chlorosuccinimide PA1 NIS=N-iodosuccinimide PA1 NMP=N-methylpyrrolidone PA1 NSAID=non-steroidal anti-inflammatory drug PA1 PCC=pyridinium chlorochromate PA1 PDC=pyridinium dichromate PA1 PEG=polyethyleneglycol PA1 Ph=phenyl PA1 r.t.=room temperature PA1 rac.=racemic PA1 Tf=trifluoromethanesulfonyl=triflyl PA1 Tf0=trifluoromethanesulfonate=triflate PA1 THF=tetrahydrofuran PA1 TLC=thin layer chromatography PA1 Ts=p-toluenesulfonyl=tosyl PA1 TsO=p-toluenesulfonate=tosylate PA1 Tz=1H (or 2H)-tetrazol-5-yl PA1 SO.sub.2 Me=methyl sulfone PA1 SO.sub.2 NH.sub.2 =sulfonamide PA1 Me=methyl PA1 Et=ethyl PA1 n-Pr=normal propyl PA1 i-Pr=isopropyl PA1 n-Bu=normal butyl PA1 i-Bu=isobutyl PA1 s-Bu=secondary butyl PA1 t-Bu=tertiary butyl PA1 c-Pr=cyclopropyl PA1 c-Bu=cyclobutyl PA1 c-Pen=cyclopentyl PA1 c-Hex=cyclohexyl PA1 bid=bis in die=twice daily PA1 qid=quater in die=four times a day PA1 tid=ter in die=three times a day PA1 0, 15min, 30min, 1 h, 2 h, 4 h, 6 h PA1 PEG 200/300/400: restricted to 2 mL/kg PA1 Methocel 0.5% -1.0%: 10 mL/kg PA1 Tween 80: 10 mL/kg PA1 0, 5 min, 15min, 30min, 1h, 2 h, 6 h PA1 or 0, 5 min, 30min, 1 h, 2 h, 4 h, 6 h. PA1 Dextrose: 1 mL/kg PA1 Moleculosol 25%: 1 mL/kg PA1 DMSO (dimethylsulfoxide): Restricted to a dose volume of 0.1 mL per animal PA1 PEG 200: Not more than 60% mixed with 40% sterile water-1 mL/kg
U.S. Pat. No. 5,474,995 (Dec. 12, 1995) and World Patent Application 95/00501 (Jan. 5, 1995) disclose compounds represented by Formula A as being useful in the treatment of COX-2 mediated diseases, by virtue of their selective inhibition of COX-2 rather than COX-1. We have now discovered that a subset of the compounds represented by A, in which --X--Y--Z-- is --C(O)CH.sub.2 CH.sub.2 -and R.sup.2 is pyridinyl or substituted pyridinyl show unexpectedly superior selectivity for the inhibition of COX-2 over COX-1 and/or superior potency as compared to the closest species disclosed in 95/00501. This subset of compounds is the subject of the present invention and is represented by Formula I. ##STR2##
Of the 150-plus specific compounds disclosed in U.S. Pat. No. 5,474,995 and World Patent Application 95/00501 only 10 of them are cyclopentenones, and none of these latter is a pyridinyl cyclopentenone. Furthermore, among the variety of specific compounds disclosed, only one of them contains a heterocyclic group in the place of R.sup.2, and that group is quinoline, not pyridine.